The principal aim of this proposal is to determine the role of the sympathetic nervous system in the development of hypertension. These studies will emphasize adrenergic function and vascular responsiveness in the intact animal and in isolated vascular smooth muscle. Regional and organ vascular resistances will be determined in the spontaneously hypertensive rat of Okamoto and Aoki (SHR) during sympathetic neuronal stimulation or inhibition and after chronic pharmacologic sympathectomy. Cardiac output and its distribution will be measured in conscious intact rats by the direct Fick procedure and radioactive microsphere technique, respectively. Vascular organ resistance will be determined from arterial pressure and respective organ blood flow rate, and organ flow will be calculated from cardiac output and its organ distribution. In vitro vascular smooth muscle preparations will be used to obtain a more complete understanding of the adrenergic parameters regulating vascular reactivity. Vascular contractile responses to exogenous norepinephrine (NE) and neurogenic NE, neuronal uptake of tritiated-NE, endogenous content of NE and the dissociation constant of the NE receptor complex will be investigated in a variety of isolated arterial and venous smooth muscle preparations from SHR. The results of these studies will determine whether the sympathetic nervous system exerts an abnormal influence on the vasculature in the SHR and if specific organ vasculatures have abnormal responsiveness to adrenergic stimuli. Further, they will determine which facet(s) of adrenergic vascular control is altered and how this alteration(s) is manifest in different vascular tissues. Integration of the data obtained from the in vivo and in vitro studies will provide a more comprehensive understanding of the role of the sympathetic nervous system in the pathophysiological circulatory alterations in hypertension and a more rational basis for treatment of hypertensive vascular disease.